Ureylenethiophane carboxylic acids and esters and methods of preparing same



' 'TVUNITEDSTAT Patented Nov. 9, i948 UREYLENETHIOPHANE CARBOXYLIG ACIDS =METH ODS F PREPAB AND ESTERS AND MINGSAME Y Bernard. R Bake r, Nanuet assignor', mesne assignments, to American Cyanamid Company, New york, N, X, a corporation of a a No Drawing. gApplication July 16,1545, A

Serial No. 605,467 V h 1 The present invention relates to new organic compounds and to methods of preparing the same. More particularly, itrelates to ureylenethiophane carboxylic acids and to esters and salts thereof.

The novel compounds which can be prepared by l methods of the present invention may be illustrated by the following, general formula:

wherein X is a member of the group consisting of hydrogen, aliphatic and aromatic radicals, R is a member of the group consisting of hydrogen, alkyl and salt formingradicals and R and R" are members of the group consisting of hydro-.

gen, carboxyalkyl and carb alkoxyalkyl radicals.

The compounds of the present invention are white crystalline solids.

esters they are soluble in chloroform, carbon tetreclaims. (c1. zen-3.29)

methoxythiophahe-d-c arboxylic. acid, (fl -carbethoxyethyl) -3-carbethoxythiophane ,4 car- .boxylic acid, Z-carbomethoxymethyl 3 Warhomethoxythiophaneh-carboxylic acid, f2-carbethoxymethyl-3-carbethoxythiophane 4 4 ,carboxylic acid, 3-carbomethoxythiophane 4 carboxylic acid, 3 carbethoxythiophane 4 carboxylic acid, 2- (a-carbomethoxybutyl) -3.-carboxy-4-carbomethoxythiophane, 2 (ycarbethoxypropyl) -3- carboxy- 4 carbethoxythiophane, 2: ifl carbo- .methoxyethyl) -3-carboxy= i carbornethoxythio- In the form of their rachloride, benzene, etc. They are relatively insoluble in water in the form of theirestersand acids; but are soluble 'inthe form oi their alkali salts, v

I prepare the compounds of the present invention by reacting a 3 or 4 -carboxythiophane with,

thionyl chloride to form a thiophaneacid chloride. The acid chloride is reacted with an alkali metal azide giving an azide derivative which on heating rearranges to an isocyanate derivative. This derivative treated with ammonia or a primary.

amine gives a substituted ureylenethiophane. Aromatic amines such as aniline, halogenated anilines, toluidines, naphthyl'amines, etc., are preferred, as the products obtained are crystalline solidseasily purified. However, primary aliphatic amines suchas, mono ethyl amine, mono ethanol amine, lauryl amine, stearyl amine,etc.,may be employed if desired.

. bokylie acid, 2- (y-carbomethoxypropyl) -3-carbo-' Theintermediates which I prefer to use incarrying out my invention are prepared bythe selec tive hydrolysis of a thiophane dior tricarboxylic acid ester to a mono carboxythiophane as shown in my copending application Serial No. 605,468 filed July 16, 1945. Among these may be specifically mentioned: 2-(5-carbomethoxybuty1) -3- carbomethoxythiophanei-carboxylic acid, 2-(6- carbethoxybutyl) -3- carbethoxythiophane-fi car- 'methoxythiophane-l-carboxylic acid, am arbetho cypropyl) 3 carbethoxythiophane 94} carboxylic acid, 2-(B-carbomethoxyethy1)-3-carboibethoxythiophanaand the like.

such as benzene-petroleum ether.

phane. i.2carbethoxymethy1-3-carboxy -4. car- In preparingthe compounds of my invention I :heat :a ,carboxythiophane such as those listed above,- with thionyl chloride'in. a solvent such as' benzene, chloroform, ether, carbon! tetrachloride; etc. ;;Thetemperature Ican use isirom about 20 to about 12090.; I prefer to use-refluxingtemperatures and to heat the reaction mixture from about-10 minutes to aboutfiOminutes; After re- 1 moval of the solvent the residue is taken up in acetone: andcooled to from 0'to 25, aqueous solutionfiof an alkali metal azide is added and :the reaction mixture is kept preferably between 0 and 25. .C. for from one-half hour to about two hours. The reaction mixture is diluted withwater and extracted with a solvent such as chloroform, benzene 'or-trichlorethylene The chloroform ,ex-

- tractsdaredried. and then refluxed for. from 15 1 minutes to GOminutes. The amine is added tothe reaction mixture which is maintained atatemperature of from Off to 80 C. for aperiod of from about 5 minutes toabout60 minutes. a

. reactionproduct may be purified by washingwith dilute hydrochloric. acid, evaporating. the

solvent and recrystallizing the residue irom as'olvent such as methanol or afmixture of solvents @The compounds prepared by methods of'the present invention are inithe, form oftheir car- L v boxylic acid esters. I f the acids themselves are desired they can be prepared by heating the esters irra solvent in the presence cf an alkali to obtain. salts andgacidifying to liberatethe acids as shown in the specific examples. x1:

The compounds of the present invention are useful as intermediates in the preparation of antivitaminsand vitamins, such as biotin.

Qur invention will novvfhe illustrated in greater detailby means of the following specific examples,

. in' which representative ureylenethiophanes are .p e a e i om on b9 h c a es f I will 1mu dersto0d, \of' course, that these examplesare givenfor purposes of illustration and are not'to be considered as limiting my invention to the particular details described therein.

stirred with 0.25 g. of sodium'azide in 7-=cc: of

water for one hour at C., then diluted with water and extracted with chloroform. The dried extract was refluxed for thirty minutes," treated with 1 cc. of aniline and evaporated." 'iher'esidue,v

dissolved in benzene, wasw'aslied with" dilute hydrochloric acid and evaporated. The residue was purified by recrystallization from abeiizen'e The product;-"2- (8 petroleum ether mixture.

4 and added dropwise with stirring and ice cooling to a solution of 2 g. of sodium azide in cc. of water. After being stirred one hour at 0 C., the mixture was diluted withseveral volumes of water and extracted twice? "wi th'= clilordfor'm. The chlorofoi'nisolution, dried overanhydrous calcium chloride at 0 C. was then refluxed for one hour, treated with 8 cc. of aniline and refluxed five-minutes more. The solution was washed successivehr"with dilute hydrochloric acid, dilute sodium bidai' bdna'te and water. Evaporation gave an oil which crystallized on the addition of ether. A. yieldiof 3.6 g; (64%) of trans -3-carbomethoxymelting point"'o'f 1"30-134 C.

The ester was saponified to trans-4-uranilinothiophane 3 oeltboxylic acid by alcoholic alkali carbomethoxybutyl) -3-carbomethoxy-trans 4 q uranilinothiophane, was obtained as white crystj.t 1 ,,melting point 121-124 C. I 'Tl i iirdductprepared' above when saponified "1 th dilute alcoholic alkali in 'the'usual manner (6 carb'oiiybutylJ -i-urani1i nothiophane-3- -iboi'ryl ic acid. melting point-190'l91 C. composition.

, .--E:tample 2 I 'ature oi 11:3" g? of crude 2 '(8-carbomethyl) 3 carbofiiethoXythiophane trans '4 Iifien was refliiXed for fifteen minutes, poi-'ated-to dryne vacuo (bath 50 0.). The evaporations repeated-" with' '-cc.- of flienZeT he. The"resitluat'acidchloride, cooled in pwise with stirring and icecooling to a of-3.1 g. of sodium a'zide'in 50 cc. of water tie that the --temperature was just After being "stirred onehour at'O" C.,

fat-366d twice with chloroform. The actsafter being" dried over anhydrous calum chloride at 0 C.,"'were refluxed for thirty IiiitSQt'lGted with 12 "cc." of aniline and reochl'ondacid, thesolution was evaporated-to "S andt'hTeSidHe crystallized from 60 CC.

thanol'. Theproduct was collected on a filter nd'washed with'ice'coldmethanol. Ayield 0152 (t carbomethoxybutyl) -3-c'arbometham ne-4:uianiimothiophane Was-obtained as "'firyjstalliiiniaitllal.

1 Example 3 fire t at solution 'of 2.6 g". of z' owarmmam 'butyl)" =3 carbomethoxy transi-uranilindv hane into-cent methanol was added 15 cc. of10% sodium hydroxide solution. After being boiled on astean'ibath for onehou'r, during which time most of the methanol evaporated, the soluw 'dililtedwith water, clarifiedwith Norite ed. The product was collectedon' a I a 181d of 2.2 g."(92'%) of Z-(S-carbOXy- 3buryingmemory-trans 4 4 4 uran'ilinothiophane was "obtained having a-melting point of 182- V Example 4 A mixture of 3.8 g. of crude 3-carbomethoxythiophane-transi-carboxylic; acid, 15 .cc. of benzene and-ice. of thionyl chloride was refluxed .iorteh minutes then evaporated to dryness in wacuo (bath 50 C'.)." The evaporation was re- {pated with mac. more of benzene. The residue,

{cooled ice. was. dissolved in 20cc; of acetone oxtiic aciaf ia cc. of thiohyl chloride and50 was-dissoivedm 50 cc; of acetone and 's' diluted with several volumes of u-fis' Ioh'ger. Washed with dilute in-the usual manner. White crystals were obtainedmelting at 176 C. with decomposition.

1. Chemical compounds having the general formula:

ENCONH-X n a i -H.o--

o.o-oyoniv 1 i 2.:Chemical compounds havingthe general "formulaz e i I r nuco wncta. i1

rr-( il O-R H s H wherinR is a carboxyalkyl radical. y. 1 3. a 2- (delta c'arboinethoxybutyl3 -3-catboniet hoxjy i-'uraiiilinothiophane. 1.

4.-.' Z-(deltfi-c'afbdXybfltYl) -3-carboxy-4-'urani1- incithiophane. .5. 2 -.(delta carboxybutyl). 3. -uranilinothi0- pnanei-earboxync acid. r 5 6. A'metliod' of preparing compounds-"liaving the'forin'ula: I l

' HNC ONH-X H c fd -ooozi =n'- c o-R" H "XS/ '\H wherein X is a membenof thelgroupcoif nor hydrogen, alkyl and aryl radicals', R is a meni- 'berl oi'ith'e 'group consisting of hydrogen,,alliyl"aild alkali metal radicals and R" and R" al. 'mlilbls 1 of the group consisting. of hydrogen, carboiiyfalliyl and"'caifbalko'xyalkyl radicals which comprises mixing a compou'nd having the formula:

"CODE-000R 'pr imarsi iaikyl amines, primary 'az'yr airlines and 4"-iiiraii-ilinothio'phane was obtained having a.

ammonia, in a solvent for said carboxythiophane. '7. A method of preparing compounds having the formula: i

HNCONH-X HCCCOOR wherein X is a member of the group consisting of hydrogen, alkyl and aryl radicals, R, is a member of the group consisting of hydrogen, alkyl and alkali metal radicals and R, and R. are members of the group consisting of hydrogen, carboxyalkyl and carbalkoxyalkyl radicals which comprises suspending a compound having the formula:

COOH COOR wherein R, R and R" are as defined above, in a solvent for said carboxythiophane and successively reacting with thionyl chloride at a temperature of 20 C. to 120 C., an alkali metal azide at a temperature of 0 C. to 25 C. and a member of the group consisting of primary alkyl amines, primary aryl amines and ammonia, at a temperature of from 0 C. to 80 C.

8. A method of preparing Z-(delta-carbomethoxybutyl) -3-carbomethoxy-4-urani1inothiophane which comprises mixing Z-(delta-carbomethoxybutyl) -3- carbomethoxythiophane -4=- carboxylic acid successively with thionyl chloride, sodium azide and aniline in a solvent.

9. A method of preparing Z-(delta-carboxybutyl) -3-car-boxy-4-urani1inothiophane which comprises mixing 2-(delta-carbomethoxybutyl) 3-carbomethoxythiophane-4-carboxylic acid successively with thionyl chloride, sodium azide and aniline in a solvent, hydrolyzing and recovering said 2- (deltacarboxybutyl) -3carboxy-4-urani1- inothiop hane from the reaction mixture.

10. A method of preparing Z-(delta-carboxybutyl) -3uranilinothiophane-4-carboxylic acid which comprises mixing Z-(delta-carbomethoxybutyl) 3-carboxyi-carbomethoxythiophane successively with thionyl chloride, sodium azide and wherein R is an alkyl radical and R" is a carbalkoxyalkyl radical.

12. A method of preparing compounds having the formula:

HNCONHCaH5/H n-o (J-ODOR wherein R is an alkyl radical and R" is a carbalkoxyalkyl radical which comprises mixing a 2-carbalkoxyalkyl-3-carba1koxythiophane-4- carboxylic acid successively with thionyl chloride, sodium azide and aniline in a solvent for said carbalkoxythiophane.

BERNARD R. BAKER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,382,418 Hoffman Aug. 14, 1945 2,400,436 Patterson May 14, 1945 

